Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare but serious disease with poorly understood mechanisms. Here we report that patients with EGPA have elevated levels of TSLP, IL-25, and sST2, well characterized cytokine “alarmins” that activate or modulate type 2 innate lymphoid cells (ILC2s). Patients with active EGPA have a concurrent reduction in circulating ILC2s, suggesting a role for ILC2s in the pathogenesis of this disease. To explore the mechanism of these findings in patients, we established a model of EGPA in which active vasculitis and pulmonary hemorrhage are induced by IL-33 administration in predisposed, hypereosinophilic mice. In this model, induction of pulmonary hemorrhage and vasculitis is dependent on ILC2s and signaling through IL4Ra. In the absence of IL4Ra or STAT6, IL-33-treated mice have less vascular leak and pulmonary edema, less endothelial activation, and reduced eotaxin production, cumulatively leading to a reduction of pathologic eosinophil migration into the lung parenchyma. These results offer a mouse model for use in future mechanistic studies of EGPA, and suggest that IL-33, ILC2s and IL4Ra signaling may be potential targets for further study and therapeutic targeting in patients with EGPA.
Maya E. Kotas, Jérémie Dion, Steven Van Dyken, Roberto R. Ricardo-Gonzalez, Claire J. Danel, Camille Taillé, Luc Mouthon, Richard M. Locksley, Benjamin Terrier
The Janus kinase/signal transducers and activators of transcription (JAK/STAT) are key intracellular mediators in the signal transduction of many cytokines and growth factors. Common γ chain cytokines and interferon-γ that use the JAK/STAT pathway to induce biological responses have been implicated in the pathogenesis of alopecia areata (AA), a T cell–mediated autoimmune disease of the hair follicle. We previously showed that therapeutic targeting of JAK/STAT pathways using the first-generation JAK1/2 inhibitor, ruxolitinib, and the pan-JAK inhibitor, tofacitinib, was highly effective in the treatment of human AA, as well as prevention and reversal of AA in the C3H/HeJ mouse model. To better define the role of individual JAKs in the pathogenesis of AA, in this study, we tested and compared the efficacy of several next-generation JAK-selective inhibitors in the C3H/HeJ mouse model of AA, using both systemic and topical delivery. We found that JAK1-selective inhibitors as well as JAK3-selective inhibitors robustly induced hair regrowth and decreased AA-associated inflammation, whereas several JAK2-selective inhibitors failed to restore hair growth in treated C3H/HeJ mice with AA. Unlike JAK1, which is broadly expressed in many tissues, JAK3 expression is largely restricted to hematopoietic cells. Our study demonstrates inhibiting JAK3 signaling is sufficient to prevent and reverse disease in the preclinical model of AA.
Zhenpeng Dai, James Chen, Yuqian Chang, Angela M. Christiano
Lupus nephritis (LN) is a serious complication occurring in 50% of patients with systemic lupus erythematosus (SLE) for which there is lack of biomarkers, specific medications, and a clear understanding of its pathogenesis. The expression of calcium/calmodulin kinase IV (CaMK4) is increased in podocytes of patients with LN and lupus-prone mice and its podocyte-targeted inhibition averts the development of nephritis in mice. Nephrin is a key podocyte molecule essential for the maintenance of the glomerular slit diaphragm. Here, we show that the presence of fucose on N-glycans of IgG induces, whereas the presence of galactose ameliorates, podocyte injury through CaMK4 expression. Mechanistically, CaMK4 phosphorylates NFκB, upregulates the transcriptional repressor SNAIL, and limits the expression of nephrin. In addition, we demonstrate that increased expression of CaMK4 in biopsy specimens and in urine podocytes from people with LN is linked to active kidney disease. Our data shed new light on the role of IgG glycosylation in the development of podocyte injury and propose the development of ‘liquid kidney biopsy” approaches to diagnose LN.
Rhea Bhargava, Sylvain Lehoux, Kayaho Maeda, Maria G. Tsokos, Suzanne Krishfield, Lena Y. Ellezian, Martin Pollak, Isaac E. Stillman, Richard D. Cummings, George C. Tsokos
Both innate and adaptive immune cells are critical players in autoimmune destruction of insulin-producing β-cells in type 1 diabetes. However, the early pathogenic events triggering the recruitment and activation of innate immune cells in islets remain obscure. Here we show that circulating fatty acid binding protein 4 (FABP4) level is significantly elevated in type1 diabetes patients and their first-degree relatives, and positively correlates with the titers of several islet autoantibodies. In non-obese diabetic (NOD) mice, increased FABP4 expression in islet macrophages starts from the neonatal period, well before the occurrence of overt diabetes. Furthermore, the spontaneous development of autoimmune diabetes in NOD mice is markedly reduced by pharmacological inhibition or genetic ablation of FABP4, or adoptive transfer of FABP4-deficient bone marrow cells. Mechanistically, FABP4 activates innate immune responses in islets by enhancing the infiltration and polarization of macrophages to pro-inflammatory M1 subtype, thus creating an inflammatory milieu required for activation of diabetogenic CD8+ T cells and shift of CD4+ helper T cells towards the Th1 subtypes. These findings demonstrate FABP4 as an early mediator for β-cell autoimmunity by facilitating crosstalk between innate and adaptive immune cells, suggesting that pharmacological inhibition of FABP4 may represent a promising therapeutic strategy for autoimmune diabetes.
Yang Xiao, Lingling Shu, Xiaoping Wu, Yang Liu, Lai Yee Cheong, Boya Liao, Xiaoyu Xiao, Ruby L.C. Hoo, Zhiguang Zhou, Aimin Xu
The liver is an immune-privileged organ that can deactivate autoreactive T cells. Yet in autoimmune hepatitis (AIH), autoreactive T cells can defy hepatic control and attack the liver. To elucidate how tolerance to self-antigens is lost during AIH pathogenesis, we generated a spontaneous mouse model of AIH, based on recognition of an MHC class II-restricted model peptide in hepatocytes by autoreactive CD4 T cells. We find that the hepatic peptide was not expressed in the thymus leading to deficient thymic deletion and resulting in peripheral abundance of autoreactive CD4 T cells. In the liver, autoreactive CD4 effector T cells accumulated within portal ectopic lymphoid structures and maturated towards pathogenic IFNγ and TNF co-producing cells. Expansion and pathogenic maturation of autoreactive effector T cells was enabled by a selective increase of plasticity and instability of autoantigen-specific Tregs, but not of non-specific Tregs. Indeed, antigen-specific Tregs were reduced in frequency and manifested increased IL-17 production, reduced epigenetic demethylation and reduced expression of Foxp3. As a consequence, autoantigen-specific Tregs had a reduced suppressive capacity, as compared to non-specific Tregs. In conclusion, loss of tolerance and the pathogenesis of AIH were enabled by combined failure of thymic deletion and peripheral regulation.
Max Preti, Lena Schlott, David Lübbering, Daria Krzikalla, Anna-Lena Müller, Fenja A. Schuran, Tobias Poch, Miriam Schakat, Sören Weidemann, Ansgar W. Lohse, Christina Weiler-Normann, Marcial Sebode, Dorothee Schwinge, Christoph Schramm, Antonella Carambia, Johannes Herkel
Tenascin-C, an extracellular matrix protein that has proinflammatory properties, is a recently described antibody target in rheumatoid arthritis. In this study, we utilized a systematic discovery process and identified five novel citrullinated tenascin-C (cit-TNC) T cell epitopes. CD4+ T cells specific for these epitopes were elevated in the peripheral blood of subjects with rheumatoid arthritis and showed signs of activation. Cit-TNC-specific T cells were also present among synovial fluid T cells and secreted interferon-γ. Two of these cit-TNC peptides were recognized by antibodies within the serum and synovial fluid of individuals with RA. Detectable serum levels of cit-TNC reactive antibodies were prevalent among subjects with RA and positively associated with cyclic citrullinated peptide (CCP) reactivity and the HLA shared epitope. Furthermore, cit-TNC reactive antibodies were correlated with rheumatoid factor and elevated in subjects with a history of smoking. Taken together this work confirms cit-TNC as an autoantigen that is targeted by autoreactive CD4+ T cells and autoantibodies in patients with RA. Furthermore, our findings suggest that a unique set of epitopes recognized by both CD4+ T cells and B cells have the potential to amplify autoimmunity and promote the development and progression of rheumatoid arthritis.
Jing Song, Anja Schwenzer, Alicia Wong, Sara Turcinov, Cliff Rims, Lorena Rodríguez-Martínez, David Arribas-Layton, Christina Gerstner, Virginia S. Muir, Kim S. Midwood, Vivianne Malmström, Eddie A. James, Jane H. Buckner
Reestablishing an appropriate balance between T effector cells (Teff) and T regulatory cells (Treg) is essential for correcting autoimmunity. Multiple Sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease characterized by neuroinflammation, demyelination, and neuronal degeneration, in which the Teff:Treg balance is skewed toward pathogenic Teff cells, Th1 and Th17 cells. Signal transducer and activator of transcription 3 (STAT3) is a key regulator of Teff:Treg balance. Using the structure-based design, we have developed a novel small-molecule prodrug LLL12b that specifically inhibits STAT3 and suppresses Th17 differentiation and expansion. Moreover, LLL12b regulates the fate decision between Th17 and Tregs in an inflammatory environment, shifting Th17:Treg balance toward Tregs and favoring the resolution of inflammation. Therapeutic administration of LLL12b after disease onset significantly suppresses disease progression in adoptively transferred, chronic, and relapsing-remitting experimental autoimmune encephalomyelitis. Disease relapses were also significantly suppressed by LLL12b given during the remission phase. Additionally, LLL12b shifts Th17:Treg balance of CD4 T cells from MS patients toward Tregs and increases Teff sensitivity to Treg-mediated suppression. These data suggest selective inhibition of STAT3 by the novel small molecule LLL12b recalibrates the effector and regulatory arms of CD4 T responses, representing a potentially clinically translatable therapeutic strategy for MS.
Saba I. Aqel, Xiaozhi Yang, Emma E. Kraus, Jinhua Song, Marissa F. Farinas, Erin Y. Zhao, Wei Pei, Amy E. Lovett-Racke, Michael K. Racke, Chenglong Li, Yuhong Yang
Ginger is known to have anti-inflammatory and anti-oxidative effects, and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report anti-neutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to demonstrate a protective role for ginger-derived compounds in the context of lupus, and importantly provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.
Ramadan A. Ali, Alex A. Gandhi, Lipeng Dai, Julia K. Weiner, Shanea K. Estes, Srilakshmi Yalavarthi, Kelsey Gockman, Duxin Sun, Jason S. Knight
Clinical trials of biologic therapies in type 1 diabetes (T1D) aim to mitigate autoimmune destruction of pancreatic beta cells through immune perturbation and serve as resources to elucidate immunological mechanisms in health and disease. In the T1DAL trial of alefacept (LFA3-Ig) in recent onset T1D, endogenous insulin production was preserved in 30% of subjects for two years post-therapy. Given our previous findings linking exhausted CD8 T cells to beneficial response in T1D trials, we applied unbiased analyses to sorted CD8 T cells to evaluate their potential role in T1DAL. Using RNA-seq, we found that greater insulin C-peptide preservation was associated with a module of activation- and exhaustion-associated genes. This signature was dissected into two distinct CD8 memory populations through correlation with clustered cytometry data. Both populations were hypo-proliferative, shared expanded TCR junctions, and expressed exhaustion-associated markers including TIGIT and KLRG1. The populations were distinguished by reciprocal expression of CD8 T and NK cell markers (GZMB, CD57 and inhibitory KIR genes), versus T cell activation and differentiation markers (PD1 and CD28). These findings support previous evidence linking exhausted CD8 T cells to successful immune interventions for T1D, while suggesting multiple inhibitory mechanisms can promote this beneficial cell state.
Kirsten E. Diggins, Elisavet Serti, Virginia S. Muir, Mario G. Rosasco, TingTing Lu, Elisa Balmas, Gerald T. Nepom, S. Alice Long, Peter S. Linsley
Transient partial remission, a period of low insulin requirement experienced by most patients soon after diagnosis has been associated with mechanisms of immune regulation. A better understanding of such natural mechanisms of immune regulation might identify new targets for immunotherapies that reverse T1D. In this study, using Cox model multivariate analysis we validate our previous findings that patients (n = 84) with the highest frequency of CD4+ CD25+CD127hi (127-hi) cells at diagnosis experience the longest partial remission and we show that the 127-hi cell population is a mix of Th1- and Th2-type cells with a significant bias towards anti-inflammatory Th2-type cells. In addition, we extend these findings to show that patients with the highest frequency of 127-hi cells at diagnosis are significantly more likely to maintain beta-cell function. Moreover, in patients treated with Alefacept in the TIDAL clinical trial, the probability of responding favorably to the anti-inflammatory drug was significantly higher in those with a higher frequency of 127-hi cells at diagnosis than those with a lower 127-hi cell frequency. These data are consistent with the hypothesis that 127-hi cells maintain an anti-inflammatory environment that is permissive for partial remission, beta-cell survival and response to anti-inflammatory immunotherapy.
Aditi Narsale, Breanna Lam, Rosita Moya, TingTing Lu, Alessandra Mandelli, Irene Gotuzzo, Benedetta Pessina, Gian Maria Giamporcaro, Rhonda Geoffrey, Kerry Buchanan, Mark Harris, Anne-Sophie Bergot, Ranjeny Thomas, Martin J. Hessner, Manuela Battaglia, Elisavet Serti, Joanna D. Davies
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